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  • This Perspective details how genome-wide association studies and metabolomics enabled the discovery of structures, bioactivities and pathways of modular metabolite biosynthesis originates from the ‘hijacking’ of conserved detoxification mechanisms by nematodes.

    • Chester J. J. Wrobel
    • Frank C. Schroeder
  • This perspective proposes general strategies for phase-separation-related biological studies, including proper experimental designs to validate and characterize phase-separation phenomena, connections to biological functions and some caveats to avoid common misunderstandings.

    • Yifei Gao
    • Xi Li
    • Yi Lin
  • Loss of myelin causes neurological symptoms for patients with multiple sclerosis. This Perspective details how phenotypic screening has accelerated discovery efforts toward potential ‘remyelinating therapeutics’.

    • Andrew V. Caprariello
    • Drew J. Adams
  • Emerging evidence shows that ubiquitination can occur on nonlysine residues and nonproteinaceous substrates. This perspective summarizes the recent discoveries in noncanonical ubiquitination and advocates the development of chemical biology tools for new substrate identification and mechanistic dissection.

    • Daniel R. Squair
    • Satpal Virdee
  • This Perspective discussed selective partitioning behaviors of biomolecules and small molecules and proposed that understanding the chemical properties that control their interactions within the condensates would promote drug development.

    • Henry R. Kilgore
    • Richard A. Young
  • New research has revealed a wealth of small molecules that target cancer-specific metabolic vulnerabilities by targeting allosteric sites. Here, a Perspective discusses how their application has provided insights into cancer metabolism and therapy.

    • Daniel M. Kremer
    • Costas A. Lyssiotis
  • Synthetic receptor signaling systems have evolved as platforms for user-controlled programming of cellular functions. This Perspective reviews these advances and defines a metrics-based engineering workflow to support future engineering efforts.

    • Janvie Manhas
    • Hailey I. Edelstein
    • Leonardo Morsut
  • This Perspective summarizes the known types of ligand-controlled ribozymes and riboswitches and discusses the reasons why allosteric ribozymes formed by fusion of RNA enzymes and RNA aptamers are rare in today’s biological systems.

    • Shanker S. S. Panchapakesan
    • Ronald R. Breaker
  • This Perspective introduces chemical biologists to potentially useful nanotechnologies, aims to inspire nanotechnologists to address questions relevant to chemical biology, and identifies possible opportunities for the two fields to collaborate.

    • Ryan M. Williams
    • Shi Chen
    • Daniel A. Heller
  • The conformational cycle of a bacterial voltage-gated sodium channel as it transitions from resting to activated open to inactivated closed states can be constructed from various crystal structure snapshots.

    • William A. Catterall
    • Goragot Wisedchaisri
    • Ning Zheng
  • The difficulty of antibiotic discovery posed by the double-membrane cell envelope of Gram-negative bacteria and active drug efflux requires better understanding of bacterial permeability and compound accumulation, and more diverse chemical libraries.

    • Shibin Zhao
    • Justyna W. Adamiak
    • Derek S. Tan
  • The Hedgehog (Hh) receptor PTCH1 uses its transporter-like function to inhibit the GPCR SMO by limiting the pool of accessible membrane cholesterol. Cholesterol acts as a ligand for SMO to activate downstream signaling.

    • Arun Radhakrishnan
    • Rajat Rohatgi
    • Christian Siebold
  • This Perspective highlights the evolution from the use of detergents to detergent-free membrane mimetics, as well as advances in structure determination and mass spectrometry that have allowed new insights into regulation and function of membrane proteins in native-like lipid environments.

    • Dror S. Chorev
    • Carol V. Robinson
  • This Perspective highlights emerging themes in the inter-regulation of the genome and metabolism via chromatin, including nonenzymatic histone modifications, cofactor-promiscuous chromatin-modifying enzymes, and subnucleocytoplasmic metabolite pools.

    • Katharine L. Diehl
    • Tom W. Muir
  • This historical Perspective on continuous directed evolution focuses on laboratory approaches that enable greater understanding of evolving molecular populations and offer investigators tools to guide the emergence of new biomolecular systems.

    • Mary S. Morrison
    • Christopher J. Podracky
    • David R. Liu
  • This Perspective describes the chemical and biophysical principles common to all bifunctional, proximity-inducing small molecules. It also discusses the underappreciated diversity of their chemical structures and biological mechanisms.

    • Christopher J. Gerry
    • Stuart L. Schreiber